The ?-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) favorably impact mitochondrial dysfunction and chronic inflammation in heart failure (HF). Treatment with DHA+EPA alters cardiac phospholipid composition by decreasing arachidonic acid (a pro-inflammatory fatty acid) and increasing DHA and the mitochondrial phospholipid cardiolipin, with is associated with improved LV function. Evidence for clinical effectiveness of DHA+EPA in HF patients comes from the GISSI-HF trial, in which a low dose of DHA+EPA (0.85g/day) modestly but significantly reduced mortality and hospitalization in HF patients. Our data suggest that a much higher dose (~3g/d) maybe ideal in HF patients, as is currently recommended for treatment of hypertriglyceridemia (3.4 g/day). Fish oil supplements contain a mix of DHA and EPA, however we postulate that DHA is superior to EPA in improving mitochondrial function and suppressing inflammation, and thus DHA should be used to treat HF. We found that DHA is more readily incorporated into tissue phospholipids than EPA, particularly in cardiac mitochondrial phospholipids like CL. Furthermore, DHA should be superior at decreasing arachidonic acid and inflammation. Thus our goal in Stage 1 is to determine if DHA is superior to EPA or DHA+EPA in increasing CL, improving mitochondrial function, decreasing arachidonic acid, suppressing inflammation, and prevent progression of HF Studies to evaluate this hypothesis will be performed in well established animal models of HF and in patients. Stage 1 has Specific Aims: 1) Determine if DHA is superior to EPA or DHA+EPA in its effects on LV remodeling in a large animal model of systolic HF. 2) Determine if DHA has a more beneficial impact than EPA or DHA-FEPA on survival, mitochondrial dysfunction, and LV remodeling in rodents with HF. 3) Conduct studies in humans to determine if DHA results in more favorable alterations in cardiac phospholipids than does DHA+EPA. 4) Prepare protocol and consortiums for the Stage 2 clinical study. RELEVANCE (See instructions): Despite aggressive treatment, patients with heart failure have a poor prognosis. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acids found in fish oils, may prevent the progressions of heart failure through mechanisms that are not addressed with current drugs. The goal of this grant is to determine if treatment with DHA will improve clinical outcomes in patients with heart failure.